Stress Hormones Might Impact Breast Cancer Therapy
NEW YORK (Reuters Health) – Studies in vitro and in mice indicate that glucocorticoids and other 3-ketosteroids may expand the therapy-resistant cytokeratin-5-positive (CK5+) cell population in estrogen receptor-alpha-positive (ER-alpha+) breast cancers.
As Dr. Hallgeir Rui said in a statement, “The data we have collected suggests that hormones used in breast cancer treatment, which are also produced by the body in response to stress, could have a major impact on disease progression and outcomes in some patients.”
In a June 22 online paper in Oncogene, Dr. Rui, of Thomas Jefferson University, Philadelphia, and colleagues noted, “Glucocorticoids have been implicated in resistance to chemotherapy in breast cancer as well as other solid tumors, and stress-related elevation of endocrine glucocorticoids is associated with unfavorable clinical outcome in breast cancer patients.”
In particular, CK5 cells harbor the ability to resist estrogen-blocking therapy and chemotherapy. When these cells become more abundant, tumors become therapy-resistant. Dr. Rui estimates that 10% to 15% of patients with ER+ disease harbor CK5 cells.
The researchers decided to test whether members of the 3-ketosteroid family, including glucocorticoids used to treat nausea and other breast-cancer-treatment related symptoms, might also expand the population of CK5 cells.
The team exposed breast cancer cell lines to four 3-ketosteroids. Two of these, dexamethasone and aldosterone, boosted CK5-cell numbers by as much as four to seven times. The researchers also confirmed their results in human breast cancer xenografts in mice. These showed increased growth of therapy-resistant tumors in mice treated with 3-ketosteroids.
The investigators further found that this upregulation of CK5+ cells required induction of the transcriptional repressor BCL6. Prolactin also suppressed 3-ketosteroid-induction of CK5+ cells in the xenografts.
These findings, they point out, “suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring (the) efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ER alpha-positive breast cancers.”
As Dr. Rui told Reuters Health by email, “Recognizing this subtype of estrogen receptor-positive breast cancer with CK5 cells, which is on the fast-track to develop resistance to standard therapies, may open opportunities to explore alternative drugs.”
However, Dr. Rui said in the statement, “Although prolactin appears to be an excellent candidate to counteract the effect of stress hormones on women with this subtype of breast cancer, the hormone can also drive other types of breast cancer, so we must proceed with caution.” An alternative might be via inhibition of BCL6 or by seeking alternatives to steroids for controlling the side effects of chemotherapy.
“Future work,” he added by email, “will determine whether doctors should be cautious with giving glucocorticoid steroids to patients with this subtype of breast cancer.”
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